Several crucial problems must be solved to make lung transplantation a practical therapeutic modality. Our research will address these problems using laboratory animal (dog) models. We will elucidate mechanisms and mediators that cause lung allograft rejection using immunofluorescent methods, radioactive particle determinations of changes in alveolar membrane permeability, and electron microscopy. We will explore the mechanisms whereby methylprednisolone reverses lung allograft rejection using similar techniques and radiolabeled corticosteroids to clarify the localization and biotransformation of these hormones. We will develop and evaluate methods for identifying lung allograft rejection earlier, more safely, and more accurately. To this end, we will study a) transbronchial and needle lung biopsy, b) lavage sampling of alveolar material with and without tracer substances, c) various immunologic methods, and d) simultaneous skin grafting. We will use information from all the studies of mechanisms of lung allograft rejection and of its diagnosis and reversal to develop methods for effectively and safely preventing or reversing the functional consequences of lung allograft rejection. In this regard, we will also evaluate the effectiveness of nonspecific immunosuppression, tolerance, enhancement, and locally administered agents in lung allograft models. We will determine the optimal unit of lung tissue to be transplanted in emphysematous recipients by performing autografts and allografts in dogs with experimental emphysema and by studying these animals extensively. We will investigate lung preservation techniques and fox-to-dog xenografting with the hope of increasing donor lung availability.